Biological component-measuring device and method for calibrating the same

ABSTRACT

This invention provides a biological component-measuring device, enabling the operator to easily calibrate the entire device and capable of measuring biological components accurately, and a method for calibrating the device. The device measures a sample including a body fluid taken through a body fluid sampler by sending it with a pump through a sample channel to a sensor. The device further includes a calibrating liquid channel through which a calibrating liquid can be supplied to the sensor via the sample channel by a switching of a first flow path changeover valve placed in the sample channel at a location upstream of the pump and connected to the channel. The method includes introducing the calibrating liquid in the calibrating liquid channel, via other channels, into the sensor by switching the valve.

CROSS-REFERENCE TO PRIOR RELATED APPLICATIONS

This is a U.S. National Phase Application under 35 U.S.C. §371 ofInternational Patent Application No. PCT/JP2007/000466 filed Apr. 26,2007 which claims the benefit of Japanese Application No. 2006-122469filed Apr. 26, 2006 both of which are incorporated by reference hereinin their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a biological component-measuring deviceand a method for calibrating a biological component-measuring device.More particularly, the present invention relates to a hygienicbiological component-measuring device that is used for medical supportdevices and devices of this kind, which biological component-measuringdevice enables the operator to easily calibrate the entire device aswell as the sensors thereof, and to attach a channel-carrying substrateto the device easily, which improves operability. The present inventionalso relates to a method for calibrating a biologicalcomponent-measuring device, by which method the operator is able tocalibrate the entire device easily while a biological component of apatient is being measured.

2. Description of the Related Art

An example of the biological component-measuring devices that have beenconventionally used in the hospital is a glucose-measuring device bywhich the blood sugar level of a blood sample is measured. An example ofthe medical devices with a glucose-measuring device incorporated is anartificial endocrine pancreas device. Among the artificial endocrinepancreas devices, a type of artificial endocrine pancreas device thatcarries out a closed-loop control where components in the blood, whichis a body fluid, of a patient, such as glucose, are measuredcontinuously or at intervals, and liquid medicines such as glucose orinsulin are injected into the patient based on the measurement in orderto control the patient's conditions, requires accurate and safeoperation during its use, often over a long period of time.Specifically, it is said that an artificial endocrine pancreas deviceshould be capable of providing accurate measurement for a period fromabout four hours to about one week. It is very important for keeping theartificial endocrine device safe to periodically calibrate the sensorsto obtain accurate and invariable measured values, and to calculate theamount of a liquid medicine necessary to be injected into the patient.

The glucose sensor sometimes outputs inaccurate values, which is causedby variation with time in the tubes passing through a peristaltic pumpthat is placed in various channels in an artificial endocrine pancreasdevice, which channels are also called tubes because they are typicallymade of soft and elastic tubes, especially in the tubes through whichsampled blood is sent to the glucose sensor. The output of inaccuratevalues may also be caused by variation with time in the sensor per se;the output data or measured values themselves are inaccurate.

Therefore, the sensor of a conventional artificial endocrine pancreasdevice is periodically calibrated, which involves temporary stopping ofsampling blood from the patient or injecting a liquid medicine intohim/her. Specifically, for example, an indwelling needle kept in a veinof a patient is taken away from him/her and the artificial endocrinepancreas device is removed from him/her. Then, the sensors of the deviceare calibrated. After the completion of the calibration, the indwellingneedle is inserted to his/her vein and kept in it again, which isfollowed by measurement of the blood sugar level of him/her with theartificial endocrine pancreas device. The measurement provides a valueof the blood sugar level, based on which an amount of a liquid medicineis decided, and the liquid medicine in the amount is injected intohim/her.

JP 58-152537 A discloses an invention for a blood substance-monitoringdevice that continuously measures substances in blood, which is anexample of a biological component-measuring device whose sensors can becalibrated while sampling of body fluid of a patient is being continued.According to the invention, blood is continuously sampled through anindwelling cannula kept in a vein and substances included in the bloodsample are measured. When the sensors are calibrated, the liquid to besent to the sensors is switched from the blood sample to a calibratingliquid at a location just upstream of the sensors. After the completionof the calibration, the liquid to be sent to the sensors is immediatelyreturned to the blood sample and the measurement is resumed. Blood beingsampled during the calibration is disposed of through a waste liquidchannel because the time period for the calibration is short. JP52-135795 A teaches a method of calibrating sensors forglucose-measuring devices. This invention also employs the idea ofswitching liquids to be sent to the sensors. Specifically according tothe invention, a calibrating liquid is introduced, by the switching,into the channel at a location near the sensors, downstream of a pumpplaced in the channel through which the blood sample is transferred.There are other relevant inventions. JP 58-198351 A discloses a methodof measuring a specified component of the body fluid while a sample ofthe body fluid, such as blood, is being diluted several different times.JP 54-82885 A, JP 55-21905 A, and JP 56-28765 A disclose blood sugarlevel-controlling devices that employ a specified method of controllingthe amount of insulin to be injected based on values obtained bycontinuous measurement of blood sugar level, and artificial endocrinepancreas devices.

SUMMARY OF THE INVENTION

The biological component-measuring devices mentioned hereinbefore areadvantageous because sensors are calibrated easily and quickly. However,calibration of only the sensors of a biological component-measuringdevice sometimes is not sufficient to provide accurate measurementbecause of aging of or variation with time in other units and members ofthe device. In other words, variation with time in units and members ofconventional biological component-measuring devices, other than thesensors thereof, brings variation in measured values. Calibrating thesensors only does not make variation in values measured by biologicalcomponent-measuring devices avoidable, when the flow rate of a samplevaries because of changes in pumps and/or sample channels, especiallywhen the ratio of the amount of a sample to that of a diluent ischanged.

An objective of the present invention is to provide a biologicalcomponent-measuring device which is capable of removing the problems asdescribed above and measuring biological components accurately, and thewhole of which can be calibrated easily and thoroughly. Anotherobjective of the present invention is to provide a biologicalcomponent-measuring device, various channels of which can be exchangedhygienically and easily, and which is still capable of measuringbiological components. A further objective of the present invention isto provide a safe, reliable and easy method for calibrating a biologicalcomponent-measuring device.

In order to achieve the foregoing objectives, the present inventionprovides the following features.

A biological component-measuring device in which a sample including abody fluid taken by a body fluid sampler is transferred to a sensorthrough a sample channel by a pump and a biological component in thesample is measured by the sensor, which includes:

a first flow path changeover valve placed in the sample channel at alocation upstream of the pump; and

a calibrating liquid channel connected to the first flow path changeovervalve, capable of supplying a calibrating liquid to the sensor throughthe sample channel by a switching operation of the first flow pathchangeover valve.

The biological component-measuring device further includes a bodyfluid-diluting liquid channel for supplying a body fluid-diluting liquidto the body fluid sampler.

The biological component-measuring device further includes:

a second flow path changeover valve placed in the body fluid-dilutingliquid channel; and

a second body fluid-diluting liquid channel, connected to the secondflow path changeover valve, capable of mixing the body fluid-dilutingliquid in the body fluid-diluting liquid channel with the calibratingliquid by a switching operation of the second flow path changeovervalve.

The biological component-measuring device further includes a flushingliquid channel through which a flushing liquid flows, the flushingliquid channel connected with the sample channel via a third flow pathchangeover valve at a location between the body fluid sampler and thefirst flow path changeover valve, and/or between the second flow pathchangeover valve and the body fluid sampler.

The flushing liquid of the biological component-measuring device furtherincludes a predetermined concentration of biological components.

The biological component-measuring device further includes a firstdiluent channel through which a diluent for diluting the sample in thesample channel flows, the first diluent channel connected with thesample channel at a location downstream of the first flow pathchangeover valve.

The biological component-measuring device further includes a gas channelconnected to the first diluent channel or a junction of the firstdiluent channel and the sample channel.

The biological component-measuring device further includes achannel-carrying substrate, in which a sample including a body fluidtaken by a body fluid sampler is transferred to a sensor through asample channel by a pump and a biological component in the sample ismeasured by the sensor, the channel-carrying substrate including:

a substrate detachably mountable on the biological component-measuringdevice proper;

a sample channel connectable to the body fluid sampler and the sensorfor measuring a biological component in the sample including the bodyfluid taken by the body fluid sampler, the sample channel fixed to thesubstrate so as to be capable of transferring the sample to the sensorby the pump; and

a calibrating liquid channel connectable to a calibrating liquid tank,and connected to the sample channel at a location upstream of the pumpvia a first flow path changeover valve, the calibrating liquid channelfixed to the substrate so as to be capable of supplying a calibratingliquid stored in the calibrating liquid tank to the sample channel.

The substrate of the biological component-measuring device furtherincludes a body fluid-diluting liquid channel fixed thereto, connectableto a body fluid-diluting liquid tank, for supplying a bodyfluid-diluting liquid stored in the body fluid-diluting liquid tank tothe body fluid sampler.

The biological component-measuring device further including includes:

a second flow path changeover valve placed in the body fluid-dilutingliquid channel; and

a second body fluid-diluting liquid channel, connected to the secondflow path changeover valve, capable of mixing the body fluid-dilutingliquid in the body fluid-diluting liquid channel with the calibratingliquid by a switching operation of the second flow path changeovervalve.

The substrate of the biological component-measuring device furtherincludes a flushing liquid channel through which a flushing liquidflows, the flushing liquid channel connectable to a flushing liquid tankand connected with the sample channel at a location between the bodyfluid sampler and the first flow path changeover valve, and/or betweenthe second flow path changeover valve and the body fluid sampler.

The flushing liquid of the biological component-measuring device furtherincludes a predetermined concentration of biological components.

The substrate of the biological component-measuring device furtherincludes a first diluent channel through which a diluent for dilutingthe sample in the sample channel flows, the first diluent channelconnectable to a diluent tank and connected with the sample channel at alocation downstream of the first flow path changeover valve.

The substrate of the biological component-measuring device furtherincludes a gas channel connected to the first diluent channel or ajunction of the first diluent channel and the sample channel.

The calibrating liquid tank of the biological component-measuring deviceis placed at a lower level than the body fluid sampler.

The method of calibrating the biological component-measuring deviceincludes transferring the calibrating liquid from the calibrating liquidchannel to the sensor via the sample channel by a switching of the firstflow path changeover valve.

The method of calibrating the biological component-measuring devicefurther includes:

a first operation of carrying out a zero point calibration of thebiological component-measuring device by supplying the diluent to thesample channel from the first diluent channel prior to sampling abiological component;

a second operation of supplying the flushing liquid to the samplechannel while the biological component is being measured; and

a third operation of introducing the calibrating liquid in thecalibrating liquid channel into the sensor via the sample channel by aswitching of the first flow path changeover valve, without introducingthe flushing liquid into the sensor.

The method of calibrating the biological component-measuring devicefurther includes:

a first operation of supplying a first portion of the flushing liquid ata first flow rate that is larger than a flow rate of the sample, to thesample channel from the flushing liquid channel while a biologicalcomponent is being measured;

a second operation of introducing the calibrating liquid into the sensorby a switching of the first flow path changeover valve placed in thesample channel, after the first portion of the flushing liquid isintroduced into the sample channel and the sensor; and

a third operation of introducing a second portion of the flushing liquidat a flow rate smaller than the first flow rate into the sample channelat a location upstream of the first flow path changeover valve and intothe body fluid sampler during the second operation, to prevent the bodyfluid from flowing into the part filled with the second portion of theflushing liquid.

The present invention employs the arrangement in which a calibratingliquid channel through which a calibrating liquid to correct measuredvalues is supplied is connected to a sample channel via a first flowpath changeover valve at a location upstream of a pump placed in thesample channel. This arrangement makes it possible not only to calibratea sensor incorporated into the biological component-measuring device,but also to correct errors due to variation with time in other elementsof the device such as the sample channel, the pump and the sensor, whichenables the device to carry out accurate measurement at all times.Specifically, the sensor of the device sees variation with time in itsoutput, and outputs and displays inaccurate measured values. The flow ofa calibrating liquid through the elements clarifies a difference betweenthe value currently outputted by the sensor and the value initiallyoutputted by it. The biological component-measuring device is able tooutput accurate measured values by correcting outputs of the sensoraccordingly after the calibration.

A biological component-measuring device, such as an artificial endocrinepancreas device, according to the present invention is provided with abody fluid-diluting liquid channel for supplying a body fluid-dilutingliquid to a body fluid sampler. When a body fluid, such as blood, takenby the body fluid sampler is mixed with the body fluid-diluting liquid,components apt to coagulate in the body fluid such as blood may beprevented from coagulation while the sampled body fluid is beingtransferred through the sample channel to the sensor. The prevention ofthe body fluid such as blood from coagulation reduces, to an ignorableextent, variation in measured values due to blood clots developed, forexample in the sample channel, compared with initially measured valuesoutputted by the biological component-measuring device at thecommencement of measurement. Therefore the present invention makes itpossible to prevent a body fluid such as blood flowing through thesample channel from coagulating, and enables a sample made by dilutingthe body fluid with the body fluid-diluting liquid to flow through thesample channel smoothly. It is more preferable to prevent blood fromcoagulation, if the body fluid-diluting liquid includes an anticoagulantsuch as heparin. The present invention also provides a biologicalcomponent-measuring device capable of reducing the amount of a sampledbody fluid because the body fluid-diluting liquid is supplied to thebody fluid sampler, and adjusting the concentration of a component to bemeasured to a concentration within such a range that the sensor is ableto output the measured value properly.

The biological component-measuring device according to the presentinvention is provided with a second flow path changeover valve in thebody fluid-diluting liquid channel, and the second flow path changeovervalve is connected with a second body fluid-diluting liquid channel.When the second flow path changeover valve is switched, the bodyfluid-diluting liquid in the body fluid-diluting liquid channel is mixedwith a calibrating liquid flowing in the calibrating liquid channel.Once the calibrating liquid is mixed with the body fluid-dilutingliquid, a calibrating liquid diluted with the body fluid-diluting liquidflows through the sample channel and the sensor, which provides data forcalibration obtained with the calibrating liquid in a concentrationresulting from the dilution with the body fluid-diluting liquid.Therefore the present invention provides a biologicalcomponent-measuring device, calibrated several times with calibratingliquids in different concentrations, capable of outputting accuratelycorrected measured values.

Furthermore, when the first flow path changeover valve and the secondflow path changeover valve are switched simultaneously, the bodyfluid-diluting liquid is allowed to flow through the second bodyfluid-diluting liquid channel. Then, the body fluid-diluting liquidmixes with the calibrating liquid in the calibrating liquid channel, andthe mixture liquid of the calibrating liquid and the body fluid-dilutingliquid is transferred to the sensor through the first flow pathchangeover valve and the sample channel. This connection of the channelsis able to correct variation in measured values outputted by the sensor,which variation is caused by variation with time in the discharge of thepump placed in the sample channel and in that of the pump transferringthe body fluid-diluting liquid. When each of the pump for supplying thebody fluid-diluting liquid to the body fluid-diluting liquid channel,and the pump for transferring a sample to the sample channel is a pumpcomprised of a tube made of an elastic material and a member forsqueezing this tube such as a roller, examples of which may includerotary peristaltic pumps and linear peristaltic pumps, variation withtime in the inner diameter of the tube causes another variation withtime in the discharge amounts of the pumps. Such variation with time inmeasured values outputted by the sensor is corrected by the simultaneousswitching of the first and second flow path changeover valves.

The present invention employs a flushing liquid channel connected to thesample channel at a location between the body fluid sampler and thefirst flow path changeover valve, and/or connected to a branch channelat a location between the body fluid sampler and the second flow pathchangeover valve that is so placed in the body fluid-diluting channel asto make the body fluid-diluting channel bifurcate, which enables aflushing liquid drawn through the flushing liquid channel to clean theelements such as the sample channel, the body fluid sampler, and thesensor and discharge undesired matters such as clots and gelled bodyfluid as well as the sample from the biological component-measuringdevice. Therefore if the sample channel, the body fluid sampler and thesensor are cleaned when or just before a calibration is started,coagulation and/or deterioration of a body fluid such as blood in thesample may be prevented and measurement may be resumed immediately afterthe calibration. Also, the introduction of the flushing liquid into thepart of the sample channel that runs between the body fluid sampler andthe first flow path changeover valve during a calibration will preventcoagulation of the body fluid such as blood.

Moreover, when the flushing liquid includes a predetermined amount ofthe measured component of the body fluid, the transference of thisflushing liquid to the sensor provides a calibration of the sensor only.When only the sensor can be calibrated, variation with time in measuredvalues due to variation with time in the sample channel and the pumpplaced in the sample channel can be detected. When the pump is composedof a part of the sample channel and a rotary peristaltic pump thatsqueezes the part, the operator may judge from the result of thedetection that variation with time in the sample channel makes themeasured values inaccurate. S/he may also judge easily that the samplechannel should be changed to a new one.

A check valve should preferably be placed in the calibrating liquidchannel at a location upstream of the first flow path changeover valve.When the calibrating liquid channel is provided with a check valve, itmay prevent a sample taken by the body fluid sampler from flowing intothe calibrating liquid channel due to breakdown, failure, malfunction,and artificial wrong operation of the biological component-measuringdevice, and also prevent unnecessary leakage of a body fluid from theexamined living organism. Therefore the check valve ensures theprevention of possible damage to the safety of human bodies.

The body fluid-diluting liquid channel should also be provided with acheck valve. The check valve placed in the body fluid-diluting liquidchannel may prevent a sample taken by the body fluid sampler fromflowing into the calibrating liquid channel due to breakdown, failure,malfunction, and artificial wrong operation of the biologicalcomponent-measuring device, and also prevent unnecessary leakage of abody fluid from the examined living organism. Therefore the check valveensures the prevention of possible damage to the safety of human bodies.

The present invention employs a first diluent channel that is connectedto the sample channel at a location downstream of the first flow pathchangeover valve. By allowing a diluent, such as a phosphoric acidbuffer or a physiological saline, to flow through the first diluentchannel, the concentration of a component to be measured can be adjustedto a concentration within such a range that the sensor is able tomeasure it properly, and the sensitivity and accuracy of the measurementcan be enhanced through an improvement in the stability thereof. Thephosphoric acid buffer, when the biological component sensor is, forexample, a glucose sensor, ensures accurate measurement by the sensorthrough an adjustment of the pH value of a body fluid taken by the bodyfluid sampler. Also, when the flow rate of the diluent is increasedand/or the diluent includes a surfactant, the time period from thesampling of a body fluid by the body fluid sampler to the measurement bythe biological component sensor, or the time constant, can be decreased.A diluent including a surfactant not only improves the flow propertiesof a fluid, but also expedites mixing of a body fluid and a diluent.

The present invention employs a gas channel connected with the firstdiluent channel or the junction of the first diluent channel and thesample channel, which makes it possible to send an inert gas such as airor nitrogen gas to the junction of the first diluent channel and thesample channel. The introduction of an inert gas enhances the efficiencyof mixing a sample and a diluent, thereby reducing the time period forwhich a sample flows through the sample channel. The employment of thegas channel enables the device to measure sampled biological componentsquickly.

The biological component-measuring device according to the presentinvention has a biological component-measuring device proper and achannel-carrying substrate. The substrate is designed so as to bedetachably attachable to the biological component-measuring deviceproper. The channel-carrying substrate may be used as a disposablemember. The substrate is provided with at least the sample channel andthe calibrating liquid channel. One end of the sample channel, which isfixed to the substrate, is made so that the end can be detachablyattached to a body fluid sampler that is a separate member, not fixed tothe substrate. The other end of the sample channel is designed so thatit can be detachably attached to a sensor that is also a member notincluded in or fixed to the substrate. The first flow path changeovervalve, which is placed in the middle of the sample channel, is fixed tothe substrate. The substrate is fixedly equipped with the calibratingliquid channel as well. One end of the calibrating liquid channel, orthe opposite of the other end that is connected to the first flow pathchangeover valve, is detachably connected to a calibrating liquidsupplier, such as a calibrating liquid tank, which is outside thesubstrate and not included in it. Various structures may be employed forthe structure to detachably join the one end of the sample channel tothe body fluid sampler, the structure to detachably join the other endof the sample channel to the sensor, and the structure to detachablyjoin the one end of the calibrating liquid channel to the calibratingliquid tank, as long as they are able to achieve liquid-tight connectionand the connecting operation can be done easily.

A liquid sample in the sample channel, which is fixed to thechannel-carrying substrate, is transferred toward the sensor by a pump.This pump may be fixed to the substrate if it is small and has a simplestructure. The pump may also be made up of a part of the sample channeland a roller with which the biological component-measuring device properis equipped, the roller capable of squeezing the part of the samplechannel. As the pump for this biological component-measuring device maybe employed a pump capable of transferring a liquid in a channel in onedirection by the cooperation of the part of the channel and the roller.

The substrate may be fixedly equipped with a body fluid-diluting liquidchannel, a second body fluid-diluting liquid channel, a flushing liquidchannel, a first diluent channel, and a gas channel, depending on thepurposes, in addition to the sample channel and the calibrating liquidchannel.

The body fluid-diluting liquid channel serves as a channel through whicha body fluid-diluting liquid used for diluting a body fluid taken fromthe examined living organism by a body fluid sampler flows. One end ofthe body fluid-diluting liquid channel is made so that it can bedetachably connected to a body fluid-diluting liquid tank, which is amember separate from the substrate and sometimes a part of thebiological component-measuring device proper. The other end of the bodyfluid-diluting liquid channel is made so that it can be detachablyjoined to the body fluid sampler. For the structures of the respectiveends for the detachable connection may be employed those for the ends ofthe sample and calibrating liquid channels.

The reasons for supplying the body fluid-diluting liquid to the bodyfluid sampler have been explained hereinabove.

It is preferable that the sample channel and the calibrating liquidchannel, and further the body liquid-diluting channel, the second bodyfluid-diluting liquid channel, the flushing liquid channel, the firstdiluent channel, and the gas channel, depending on the purposes or atneed, should be neatly arranged on and fixed to the substrate, whichwill be attached to the biological component-measuring device proper. Itcan make wrong operations avoidable when the ends of the respectivechannels are connected to members that are not fixed to the substrate,such as the body fluid sampler, the body fluid-diluting liquid tank, thecalibrating liquid tank, and the sensor. It also enables the operator toexchange channels easily, and enhances operability and hygiene of thebiological component-measuring device.

The calibrating liquid tank should be disposed at a lower level than thebody fluid sampler, when the biological component-measuring deviceaccording to the present invention is made up of the channel-carryingsubstrate and the biological component-measuring device proper to whichthe substrate is attached, and when the device is made up differently.The disposition of the calibrating liquid tank at a lower level preventsa calibrating liquid from flowing backward in the sample channel forsome reasons and reaching the body fluid sampler, when the calibratingliquid is supplied from the calibrating liquid tank to the samplechannel via the first flow path changeover valve. In summary, arrangingthe calibrating liquid tank and the body fluid sampler so that theformer is placed at a lower location than the latter leads to theprevention of accidents such as an inflow of the calibrating liquid intothe examined living organism caused by breakdown or malfunction of thebiological component-measuring device.

The calibration method according to the present invention is capable ofcorrecting variation with time in the sample channel and the pump, andfurther variation with time in the flow rate of the diluent, as well asvariation with time in measured values caused by variation with time inthe sensor, by one calibrating operation. As a result, the operationnecessary for calibrating the entire device is simple, which reduces atime period taken to calibrate it. It is very convenient for theoperator. Also, generally, only limited materials that have proven theirsafety and appropriateness may be used for channels through whichliquids such as body fluids flow, in medical devices such as biologicalcomponents-measuring devices. A simultaneous demand on the materials isa low price. Because variation with time in the channels can becorrected, the present invention makes it possible to choose inexpensivesafe materials for the channels among a wide variety of materials thathave not been used. Furthermore, the reduction of the time period takento calibrate a biological component-measuring device also decreases atime period for which a continuous measurement is interrupted. Thebiological component-measuring device according to the present inventionis capable of measuring biological components almost continuously, andis preferably used for measuring the blood sugar level during surgeries.

The calibration method of the present invention makes it possible tocarry out a zero point calibration of the biological component-measuringdevice by supplying a diluent to the sample channel from the firstdiluent channel prior to sampling a biological component. Generally, thezero point varies very slightly during a measurement of a biologicalcomponent. Therefore if a zero point calibration is done once prior tothe measurement, it will not be necessary in many cases to carry outanother zero point calibration until the measurement is completed. Whenzero point calibrations are not carried out during the measurement, achannel normally connected to the sample channel at a locationdownstream of the sensor and a flow path changeover valve for theswitching to this channel may be omitted. Also, a flushing liquid may beintroduced into the sample channel during a measurement of a biologicalcomponent, which is followed by the introduction of a calibrating liquidinto the sensor through a switching of the first flow path changeovervalve that makes a selection between the calibrating liquid channel andthe sample channel before the flushing liquid reaches the sensor,whereby the biological component-measuring device can be calibrated.This method reduces the total time period taken to carry outcalibration.

Furthermore, the flushing liquid may include a component to be measured,for example glucose, in a predetermined amount. The use of a flushingliquid including a predetermined amount of a component being measuredmakes it possible to calibrate the sensor only. The operator is able tojudge whether the sample channel should be changed to a new one based onthe result of the calibration of the sensor only. In other words,maintenance of the biological component-measuring device can be doneexactly.

The calibration method of the present invention includes the operationalstep of introducing a flushing liquid into the sample channel at a flowrate larger than the flow rate of the sample, which is called “the firststep”, during a measurement of a biological component. The introducedflushing liquid cleans elements such as the sample channel, the bodyfluid sampler and the sensor, and discharges undesired matters such asclots and gelled body fluid as well as the sample from the biologicalcomponent-measuring device. When the flushing liquid does not includethe component being measured, a zero point calibration can be carriedout even under the condition where the body fluid sampler is connectedto the human body. The method also includes the operational step ofintroducing a calibrating liquid into the sensor by switching the firstflow path changeover valve placed in the sample channel so that thepassing of the calibrating liquid is selected, after the first portionof the flushing liquid is introduced into the sample channel and thesensor, which is called “the second step”. The use of a calibratingliquid including a particular component being measured enables thesensor to measure the component in known concentrations and to outputcorresponding measured values. The operator is able to calibrate thebiological component-measuring device as a whole, preparing a workingcurve based on these measured values and the value obtained in the firststep. The method further includes the operational step of introducing asecond portion of the flushing liquid at a flow rate smaller than thefirst flow rate into the sample channel at a location upstream of thefirst flow path changeover valve and into the body fluid sampler duringthe second step, which is called “the third step”. The third step servesto prevent the body fluid such as blood from clotting in the samplechannel between the body fluid sampler and the first flow pathchangeover valve during the calibrating operations.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic block diagram showing an embodiment of thebiological component-measuring device equipped with a bodyfluid-diluting liquid channel according to the present invention.

FIG. 2 is a schematic block diagram showing an embodiment of thebiological component-measuring device further equipped with a flushingliquid channel according to the present invention.

FIG. 3 is a schematic block diagram showing an embodiment of thebiological component-measuring device equipped with a bodyfluid-diluting liquid channel and a first diluent channel according tothe present invention.

FIG. 4 is a schematic block diagram showing an embodiment of thebiological component-measuring device equipped with a flushing liquidchannel, a body fluid-diluting liquid channel, a first diluent channeland a gas channel according to the present invention.

FIG. 5 is a schematic block diagram showing an embodiment of thebiological component-measuring device to which a channel-carryingsubstrate is attached, according to the present invention.

FIG. 6 is a schematic block diagram showing an example of a conventionalbiological component-measuring device.

FIG. 7 is an illustration showing the structure of a tube pump.

FIG. 8 is an illustration showing the structure of a pump.

FIG. 9 is a sectional view showing the structure of a mixer.

FIG. 10 is a sectional view showing the structure of a mixer, takenalong a second line perpendicular to the first line along which thesectional view of FIG. 9 is taken.

FIG. 11 is an illustration showing the structure of a pillow-typereciprocating pump.

FIG. 12 is a top view illustration of the pillow-type reciprocating pumpshown in FIG. 11, wherein a holding plate 21 e is not shown.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 1. The ReferenceNumerals

-   -   1 . . . biological component-measuring device; 2 . . . examinee;        3 a . . . body fluid sampler; 3 b . . . calibrating liquid        sucker; 4 a . . . body fluid-diluting liquid tank; 4 b . . .        diluent tank; 5 . . . sensor; 6 . . . waste liquid tank; 7 . . .        sensor signal processor; 8 . . . calibrating liquid tank; 9 a .        . . second flow path changeover valve; 9 b . . . first flow path        changeover valve; 9 c, 9 d, 9 e . . . third, fourth and fifth        flow path changeover valves; 10 . . . pump tube; 10 a, 10 b, 10        c, 10 d, 10 e, 10 f . . . pump; 11 a . . . first portion of a        sample channel; 11 b . . . second portion of a body        fluid-diluting liquid channel; 11 c . . . third portion of the        body fluid-diluting liquid channel; 11 d . . . second portion of        the sample channel, 11 e . . . third portion of the sample        channel; 11 f . . . waste liquid channel; 11 g . . . second body        fluid-diluting liquid channel; 11 h . . . calibrating liquid        channel; 11 i . . . first portion of a first diluent channel; 11        j . . . second portion of the first diluent channel; 11 q . . .        second diluent channel; 11 k . . . first portion of a flushing        liquid channel; 11 m . . . second portion of the flushing liquid        channel; 11 r . . . third portion of the flushing liquid        channel; 11 n . . . gas channel; 11 o . . . fourth portion of        the sample channel; 11 p . . . gas-discharging channel; 12 . . .        sensor signal transmission line; 13 . . . flushing liquid tank;        14, 14 a, 14 b, 14 c, 14 d . . . check valve; 15 . . . mixer; 15        a . . . mixer proper; 15 b . . . inner fluid flow space, 15 c .        . . rugged part; 16 . . . gas-liquid separator; 17 . . .        channel-joining member; 18 . . . heater; 19 . . .        channel-carrying substrate; 20 a . . . roller; 20 b . . .        rotator; 20 c . . . stick; 20 d . . . holding plate; 21 . . .        pump; 21 a . . . pressing member; 21 b . . . eccentric rotating        cam; 21 c . . . rotating shaft; 21 d, 21 e . . . holding plate;        21 f . . . hole; 21 g . . . first poppet valve; 21 h . . .        second poppet valve; 21 i . . . tube molded in the shape of a        pillow; 22 . . . pillow-type reciprocating pump

2. The Detailed Description

The present invention relates to improving a biologicalcomponent-measuring device that measures various biological componentsincluded in the body fluids of a living organism, a typical example ofwhich is a human. The body fluids in a living body include, for example,blood, urine, lymph or cerebrospinal fluid, or mixtures thereof. Thebiological components, the qualitative or quantitative analysis of whichis necessary for medical practice, may include glucose, urea, uric acid,lactose, sucrose, lactate, ethanol, glutamic acid, ammonia, creatinine,and oxygen. Medical practice may sometimes require measurement of otherproperties, such as the pH value and the oxygen concentration, of bodyfluids. In the context of the present invention, the term “biologicalcomponents” includes properties such as the pH value and the oxygenconcentration.

A biological component-measuring device is a device necessary formedical doctors and veterinarians to understand the condition of aliving organism accurately. Examples of medical support devices includeartificial endocrine pancreas devices for measuring a blood sugar levelin blood and based on the measurement results supplying insulin to aliving organism, dialyzers for dialyzing, urea concentration meters formeasuring the urea content included in the body fluids of a livingorganism, uric acid concentration meters for measuring a uric-acidcontent in the body fluids of a living organism, sugar concentrationmeters for measuring lactose and sucrose in the body fluids of a livingorganism, lactic acid concentration meters for measuring lactic acidssuch as lactate, glutamic acid concentration meters for measuring theglutamic acid content in the body fluids of a living organism, ammoniaconcentration meters for measuring an ammonia content in the body fluidsof a living organism, and creatinine concentration meters for measuringa creatinine content in the body fluids of a living organism.

These various biological component-measuring devices are necessary totake exact medical action. Thanks to the present invention, the clinicalexaminer is able to make a biological component-measuring device readyfor operation efficiently and hygienically. For the sensor included inthe biological component-measuring device to measure a biologicalcomponent may be employed various sensors depending on the kinds ofbiological components to be measured. Examples of such sensors mayinclude biosensors, such as enzyme sensors utilizing enzymes,microorganism sensors employing microorganisms, and hybrid sensorsutilizing enzymes and microorganisms. The enzyme or microorganismutilized in such a biosensor is selected depending on the target to bemeasured, or the biological component. For example, when the target tobe measured is glucose, β-D-glucose oxidase or Pseudomonas fluorecensmay be employed as biosensor. When the target is urea, urease may beemployed as biosensor; when the target is uric acid, uricase may beemployed; for lactate may be used lactate oxidase; for lactose may beemployed lactase or β-galactosidase; for ethanol may be employed alcoholoxidase or Trichosporon brassicaes; for glutamic acid may be employedglutamate dehydrogenase or Escherichia coli; and for ammonia may beemployed nitrifying bacteria.

For the sensor may be employed, for example, a biosensor made by coatinga carbon electrode with an osmium polymer, drying the coated electrodeat room temperature, applying an enzyme solution thereto to make a film,and immobilizing the enzyme by a cross-linking agent such asglutaraldehyde, when glucose is measured. This biosensor causes anoxidation reaction between peroxide and a peroxidase enzyme, which isimmobilized in the osmium polymer, and the reaction is followed by areduction reaction between the osmium polymer, the peroxidase and theelectrode. The electrode potential during these reactions is 0 mVcompared with the electrode potential of the silver-silver chlorideelectrode. Therefore the utilization of the glucose oxidase for theenzyme for the oxidation reaction leads to a quick detection of glucoseand an easy measurement of the concentration thereof. The glucose sensormay include, other than that explained above, a glucose sensor includingan osmium (II)-bipyridine complex, one including a ruthenium complex,and a glucose sensor with an electrode modified with a polypyrrole intowhich a tris-osmium complex is immobilized. Among these various glucosesensors, the biosensor employing the osmium polymer is preferable.Suitable glucose sensors are film sensors having a work electrode ofplatinum, silver or carbon, and an enzyme film of an osmium polymerimpregnated with peroxidase.

The biological component-measuring device according to the presentinvention is capable of dealing with one or more measurable biologicalcomponents. When two or more biological components are measured, thedevice should be equipped with two or more biosensors in the biologicalcomponent-measuring channel. Another way to measure several componentsmay be to make the biological component-measuring channel branch off andto provide each branch channel with one or more biosensors. The bodyfluids sampled from a living organism may be sampled body fluids as theyare, such as blood, urine, lymph and cerebrospinal fluid, or mixtures ofsuch body fluids and other liquids such as physiological saline,diluents or buffers.

The constitution of the biological component-measuring device accordingto the present invention can be explained by referring to the schematicblock diagram shown in FIG. 1. A biological component-measuring device 1according to the present invention in its basic constitution includes abody fluid sampler 3 a; a sensor 5; first, second and third portions 11a, 11 d, 11 e of a sample channel through which a body fluid istransferred from the body fluid sampler 3 a to the sensor 5; a pump 10 bplaced in fourth and fifth portions of the sample channel to forciblytransfer a sample including the body fluid that flows in the samplechannel; a calibrating liquid tank 8 in which a calibrating liquid isstored; a calibrating liquid channel 11 h to guide the calibratingliquid to the second portion 11 d of the sample channel; and a firstflow path changeover valve 9 b serving to connect the first portion 11 aof the sample channel and the calibrating liquid channel 11 h with thesecond portion 11 d of the sample channel, and to switch the connectionwith the second portion 11 d of the sample channel between the firstportion 11 a of the sample channel and the calibrating liquid channel 11h so that either of the taken sample and the calibrating liquid willflow into the second portion 11 d of the sample channel. Although thecalibrating liquid tank 8 includes the word “tank”, the “tank” means acontainer in which liquid is stored, such as a bag, a can or a box.Tanks including a body fluid-diluting liquid tank, a diluent tank, and aflushing liquid tank, which will be explained hereinafter, are also usedin the present specification to denote general containers.

Although the sensor per se may have functions of processing measuredvalues, storing them, outputting and displaying them, the device shouldpreferably have a sensor signal transmission line 12 and a sensor signalprocessor 7 to send signals outputted by the sensor through the sensorsignal transmission line 12 to the sensor signal processor 7 in whichmeasured values are processed and stored and which outputs and displaysthe measured results or sends them to other units. When the biologicalcomponent-measuring device is actually operated, a waste liquid, or asample including a body fluid after measurement by the sensor, shouldpreferably be guided to a waste liquid tank 6 through a waste liquidchannel 11 f, and then disposed of hygienically. Normally, a bodyfluid-diluting liquid, such as an anticoagulant, should be introducedinto the body fluid sampler 3 a in order to prevent a sampled body fluidfrom changing in its properties, and a sampled body fluid should bediluted with the body fluid-diluting liquid at the same time as the bodyfluid is taken. The diluted body fluid will be used as a sample to bemeasured. As shown in FIG. 1, the device should further include a bodyfluid-diluting liquid tank 4 a in which a body fluid-diluting liquid isstored, and a first portion 11 c of a body fluid-diluting channel 11 c,a second portion 11 b of the body fluid-diluting channel, and a pump 10a, through which the body fluid-diluting liquid is introduced into thebody fluid sampler 3 a. The employment of this structure should beaccompanied by the placement of a second flow path changeover valve 9 ain the first portion 11 c of the body fluid-diluting liquid channel at alocation downstream of the pump 10 a with which a second bodyfluid-diluting liquid channel 11 g is connected, so that the bodyfluid-diluting liquid can be introduced to a calibrating liquid sucker 3b that is provided to draw a body fluid-diluting liquid from thecalibrating liquid tank 8 and send it to the calibrating liquid channel11 h. The calibrating liquid sucker 3 b has a structure similar to thestructure of the body fluid sampler 3 a. The former should have such astructure that the ratio of the amount of a body fluid to that of thebody fluid-diluting liquid in the body fluid sampler 3 a is the same asthe ratio of the amount of the calibrating liquid to that of the bodyfluid-diluting liquid in the calibrating liquid sucker 3 b. Normally, asame one as the body fluid sampler 3 a should be used for thecalibrating liquid sucker 3 b, which makes the latter ratio the same asthe former ratio.

The measurement of a biological component by the biologicalcomponent-measuring device 1, and the method of calibration will now bedescribed. Firstly, a biological component-measuring device 1 in acapable condition is prepared. In this state, the first flow pathchangeover valve 9 b makes the first portion 11 a of the sample channelcommunicate with the second portion 11 d of the sample channel, andblocks the calibrating liquid channel 11 h. This operation can be doneeasily when a cross valve is used for the first flow path changeovervalve 9 b. On the other hand, the second flow path changeover valve 9 amakes the second portion 11 b of the body fluid-diluting liquid channelcommunicate with the first portion 11 c of the body fluid-dilutingliquid channel, and blocks the second body fluid-diluting liquid channel11 g. Then, the pumps 10 a, 10 b are activated, and while a bodyfluid-diluting liquid is being supplied to the body fluid sampler 3 a,the body fluid sampler 3 a transfers a sample including a taken bodyfluid to the sensor 5. In this state, the respective discharges of thepump 10 a and the pump 10 b are adjusted so that the amount of thesupplied body fluid-diluting liquid is larger than that of the sampledrawn to the first portion 11 a of the sample channel from the bodyfluid sampler 3 a. If the amount of the sample drawn to the firstportion 11 a of the sample channel is not larger than that of the bodyfluid-diluting liquid supplied to the body fluid sampler, the body fluidcannot be taken through the body fluid sampler 3 a. The bodyfluid-diluting liquid may be anything as long as it does not affectliving organisms adversely, interfere with measurement by the sensor,change a body fluid in its properties, or coagulate a body fluid.Preferable is a physiological saline or Ringer's solution. If the amountused is small, other liquids such as distilled water or a phosphoricacid buffer may be used. In order to prevent a body fluid such as bloodfrom gelling at the tip of a catheter, Ringer's solution, thephysiological saline, the distilled water into which an anticoagulant isincorporated may be used preferably. Examples of the anticoagulant mayinclude heparin, Nafamostat mesylate and urokinase.

Thus, a biological component in the taken body fluid can be measured. Ifthe measurement is continued, the biological component can be measuredcontinuously. In this specification, the taken body fluid or a solutionmade by diluting the taken body fluid with a body fluid-diluting liquidmay sometimes be called “sample”. When the biologicalcomponent-measuring device is, for example, a blood sugarlevel-measuring device, a continuous measurement over one to severaldays can be possible. However, sensors for measuring biologicalcomponents, including blood sugar level-measuring sensors, are oftenbiosensors utilizing enzymes or microorganisms as stated above. Suchsensors usually require calibration at intervals from several hours toseveral tens of hours. If calibration with such frequencies isneglected, accurate measured values often cannot be obtained. Also,channels, such as the sample channel and the body fluid-dilutingchannel, and pumps for transferring liquids are often so-calleddisposable ones from the viewpoint of hygiene, which makes themanufactures select cheap tubes such as vinyl chloride tubes orpolyethylene tubes for these elements. The elements, such as channelsand pumps, made of these cheap tubes are apt to cause variation in theflow rate of the sample and the diluting ratios due to variation withtime in the thickness of the channels, especially in the inner diameterthereof, or the transverse sectional area thereof; variation in theoperating temperature while they are being used; and variation in theproperties of the pumps. Such variations in the flow rate and thediluting ratios cannot be taken care of by calibration of the sensorsonly. Therefore, the present invention employs the method of calibratingall of the sample channel, the body fluid-diluting liquid channel, thepumps 10 b, 10 a, and the sensor 5 as a whole by introducing thecalibrating liquid from the first portion 11 a of the sample channel,which provides accurate calibration to the entire biologicalcomponent-measuring device 1. The employment of this method makes itpossible to use channels made by such materials that change in thethickness of the channels, especially the inner diameter thereof, or thetransverse sectional area thereof when the channels are used for a longtime. Generally, only limited materials that have proven their safetyand appropriateness may be used for channels through which liquids suchas body fluids flow, used in medical devices such as biologicalcomponents-measuring devices. A simultaneous demand on the materials isa low price. Because variation with time in the channels can becorrected, this embodiment makes it possible to choose inexpensive safematerials for the channels among a wide variety of materials that havenot been used. Therefore the first flow path changeover valve 9 b thatswitches between the first portion 11 a of the sample channel and thecalibrating liquid channel 11 h should be placed near the outlet of thebody fluid sampler 3 a. Furthermore, when a body fluid-diluting liquidis introduced into the body fluid sampler 3 a, the body fluid-dilutingliquid in the same amount as the body fluid-diluting liquid that wasused during the sampling of the body fluid should be introduced into thecalibrating liquid sucker 3 b by the switching of the second flow pathchangeover valve 9 a. This operation makes the ratio of the amount ofthe body fluid-diluting liquid to that of the calibrating liquid thesame as the ratio of the amount of the body fluid-diluting liquid tothat of the body fluid, which simplifies the calibration and isadvantageous.

The biological component-measuring device 1 according to the presentinvention should be used in the state where the body fluid sampler 3 ais placed at a higher level than the other parts and members such as thebody fluid-diluting liquid tank 4 a, the calibrating liquid tank 8, thesensor 5, and the waste liquid tank 6.

The communication between the body fluid sampler 3 a and the calibratingliquid tank 8 is not blocked by elements such as a tube pump. Therefore,if an actual operation of body fluid sampling is performed by abiological component-measuring device where the calibrating liquid tankis located at a higher level than the examined living organism, there isa probability that the calibrating liquid may flow into the livingorganism by gravitation, while the flow path changeover valve isswitching the channels or when malfunction occurs in the valve or otherelements. There is a weak probability that the calibrating liquid mayendanger the examinee, or the living organism, because the calibratingliquid is a solution including the same component of the livingorganism; the calibrating liquid is a glucose solution in almost thesame concentration as the glucose concentration in the living organism,when the glucose concentration is measured. However, the calibratingliquid does not require sterilization by nature. If the calibratingliquid flows into the living organism, infectious diseases might becaused by it. The calibrating tank 8 should preferably be placed at alower level than the body fluid sampler 3 a, which will leads to theprevention of such infection. In actual operations, the calibratingliquid tank 8 should preferably be placed below, for example a bed onwhich the living organism from which a body fluid is taken, such as ahuman. Because the height of the bed is typically about 45 cm, thisarrangement will be realized if the liquid level in the calibratingliquid tank 8 is set to 45 cm or less from the floor.

In summary, the body fluid sampler 3 a should be attached to a livingorganism at a higher level than the biological component-measuringdevice 1, especially the calibrating liquid tank 8, and then sampling ofthe body fluid and calibration of the biological component-measuringdevice 1 should be carried out. There is a probability that thecalibrating liquid may adversely affect the living organism if thecalibrating liquid flows backward into the living organism, as statedabove. Therefore in a state where a body fluid in the living organismand a liquid in the body fluid sampler 3 a may be exchanged, thecalibrating liquid tank 8 should be disposed at a lower level than thebody fluid sampler 3 a when the latter is attached to the livingorganism. This arrangement will check an inflow of the calibratingliquid into the living organism by gravitation, even if the firstportion 11 a of the sample channel, the first flow path changeover valve9 b or the calibrating liquid channel 11 h works wrongly, or theoperator makes some errors. However, the body fluid sampler 3 a does notalways have to be disposed at a higher level than the liquid level inthe calibrating liquid tank 8; there is no probability that thecalibrating liquid flows into the living organism, when the summation ofthe pressure head and the potential head of a body fluid, such as blood,at the position where the body fluid sampler 3 a is connected to theliving organism is larger than the potential head of the liquid level inthe calibrating liquid tank 8. Therefore when the body fluid sampler 3 ais connected to, for example a peripheral vein in which the bloodpressure is about 18 mmHg, the liquid level in the calibrating liquidtank 8 may be about 240 mm higher than the position at which the bodyfluid sampler 3 a is connected to the living organism. When the bodyfluid sampler 3 a is connected to an artery, in which the blood pressureis higher than in a vein, the calibrating tank 8 may be disposed at afurther higher level.

The waste liquid tank should be disposed so that a waste liquidnaturally drips from the waste liquid channel to the surface of theliquid in the tank, with the waste liquid channel not being in theliquid. These elements should be arranged so that a waste liquid doesnot flow back through the sample channel due to the principle of thesiphon. The pump placed in each channel preferably has a function ofpreventing backflow. Examples of such a pump may include tube pumps andlinear peristaltic pumps. These arrangement and selection make itpossible to prevent a backflow of the liquid in each channel into theliving organism caused by abnormal movements of the liquid and to checkan unexpected inflow of the liquid into the tanks, such as thecalibrating liquid tank, with which the biological component-measuringdevice is provided.

The example of the biological component-measuring device according tothe present invention shown in FIG. 2 has a flushing liquid channel 11 min addition to the device that I have explained, referring to theexample shown in FIG. 1. The flushing liquid channel 11 m, or the secondportion 11 m of the flushing liquid channel, can communicate with thefirst portion 11 a of the sample channel via a third flow pathchangeover valve 9 c, and with the second portion 11 b of the bodyfluid-diluting liquid channel via a fourth flow path changeover valve 9e. Furthermore, the calibrating liquid channel 11 h, the second portion11 b of the body fluid-diluting liquid channel, and the second portion11 m of flushing liquid channel are respectively provided with checkvalves 14 a, 14 b and 14 c. When the body fluid sampler 3 a is keptattached to the living organism during the calibration of the biologicalcomponent-measuring device shown in FIG. 1, a sample including the bodyfluid remains in the body fluid sampler 3 a and the first portion of thesample channel 11 a. When the sample remains in the device in such astate, there is a probability that the body fluid included in thesample, such as blood, may coagulate. Especially when the bodyfluid-diluting liquid is not used, or the amount of the bodyfluid-diluting liquid used for the dilution is small, the component inthe sample is prone to coagulate. The embodiment of the presentinvention shown in FIG. 2 is provided with equipment to introduce theflushing liquid in order to wash the respective insides of the bodyfluid sampler 3 a and the first portion 11 a of the sample channel whenor just before the calibrating operation is begun, so that themeasurement can be resumed immediately after the completion of thecalibration and the body fluid included in the sample is prevented fromcoagulation or deterioration. The equipment to introduce the flushingliquid into the device includes a flashing liquid tank 13, a pump 10 dfor sending the flushing liquid, the first portion 11 k, 11 m of theflushing liquid channel, the third and fourth flow path changeovervalves 9 c, 9 e, and preferably the check valve 14 c. If a pump with afunction of preventing backflow, such as a tube pump or a linearperistaltic pump, is used for the pump 10 d for sending the flushingliquid, a backflow from the sample channel or the body liquid-dilutingliquid to the flushing liquid channel should not occur principally andthe third and fourth flow path changeover valves 9 c, 9 e and the checkvalve 14 c may be omitted. However, if there is something wrong with theflushing liquid channel or the pump 10 d for sending the flushingliquid, the third and fourth flow path changeover valves 9 c, 9 e thathave the function of cross valves and the check valve 14 c effectivelyprevent backflow.

When the flushing is commenced, the pump 10 d is activated and the thirdflow path changeover valve 9 c and/or the fourth flow path changeovervalve 9 e is switched so that a flushing liquid stored in the flushingliquid tank 13 is sent to the first portion 11 k of the flushing liquidchannel, guided to the second portion 11 m of the flushing liquidchannel by the pump 13, and further introduced through the check valve14 c to the first portion 11 a of the sample channel and/or the secondportion of 11 b the body fluid-diluting channel via the third flow pathchangeover valve 9 c and/or the fourth flow path changeover valve 9 e. Apart of the flushing liquid reaches the sensor through the samplechannel and is discharged to the waste liquid tank through the wasteliquid channel. Another part of the flushing liquid flows into theliving organism through the body fluid sampler. Thus, the channels andelements such as the sample channel, the sensor and the body fluidsampler are washed with the flushing liquid, so that clots and gelledbody fluid as well as the sample are discharged from the biologicalcomponent-measuring device. This operation is called the “removal ofclots”. The first portion of the sample channel 11 a, the sensor, andthe body fluid sampler 3 a are filled with the flushing liquid, whichremoves a probability that the biological component may coagulate inthem. Then, the first flow path changeover valve 9 b and the second flowpath changeover valve 9 a are switched so that the calibrating liquid isintroduced from the calibrating liquid channel 11 h into the secondportion 11 d of the sample channel and the portion downstream thereof,which is followed by the calibration of the biologicalcomponent-measuring device 1. The third flow path changeover valve 9 cpreferably blocks the communication between the first portion 11 a ofthe sample channel and the second portion 11 m of the flushing liquidchannel, and the fourth flow path changeover valve 9 e between thesecond portion 11 b of the body fluid-diluting liquid channel and thesecond portion 11 m of the flushing liquid channel, during a normalmeasurement of a biological component.

The sensor may also be washed with the calibrating liquid other than theflushing liquid. After the completion of the washing with the flushingliquid, the first flow path changeover valve 9 b and the second flowpath changeover valve 9 a are respectively switched so that the secondportion of the sample channel and the first portion of the bodyfluid-diluting liquid channel respectively communicate with thecalibrating liquid tank 8, which keeps the first portion 11 a of thesample channel filled with the flushing liquid. Even if the pump 10 dfor sending the flushing liquid is stopped in this state, coagulationcan be prevented because it is the same as the state where the so-called“physiological saline lock” is attached to the living organism. When thepump 10 d for sending the flushing liquid is not stopped but driven soas to send the liquid little by little, for example, at a very smallflow rate, the possibility of coagulation can be further reduced.

The flow rate of the flushing liquid during the calibration should besmaller than that of the flushing liquid during the “removal of clots”operation. The introducing operation of the flushing liquid in thisstate is called the “prevention of clotting” operation. The flushingliquid is introduced at a flow rate from 5 to 500 mL/hour, preferablyfrom 100 to 300 mL/hour for about 1 to 60 seconds, preferably for about3 to 20 seconds during the removal of clots operation, while it isintroduced at a flow rate from 0.5 to 60 mL/hour, preferably from 1 to20 mL/hour during the prevention of clotting operation, with, forexample, a biological component-measuring device for a typicalartificial endocrine pancreas device. When a biologicalcomponent-measuring device has very small dimensions, an even smalleramount of the flushing liquid may be used as long as clots in thechannel can be removed and coagulation can be prevented. When there islittle or no possibility that body fluid components can coagulate evenif the sample remains in the section of the first portion 11 a of thesample channel between the third flow path changeover valve 9 c and thefirst flow path changeover valve 9 b, the calibration may be commencedat the same time as the introduction of the flushing liquid into thefirst portion 11 a of the sample channel and the body fluid sampler 3 a.For the flushing liquid may be used a liquid that are not harmful toliving organisms when it flows into them, such as a physiologicalsaline. If it is desired that the inflow of the flushing liquid into theliving organism be avoided as much as possible, the introduction of theflushing liquid may be stopped after the first portion 11 a of thesample channel and the body fluid sampler 3 a are filled with theflushing liquid. The flushing liquid may be anything as long as it doesnot change the body fluid or the sample in its properties, coagulate it,interfere with measurement by the sensor, or affect living organismsadversely if the flushing liquid flows into them. Preferable is aphysiological saline or Ringer's solution. If the amount used is small,distilled water may be used. Ringer's solution, the physiologicalsaline, the distilled water into which an anticoagulant, such asheparin, Futhan or urokinase, is incorporated may be used appropriately.The anticoagulant, however, preferably should not be used, because itaffects the antithrombogenicity mechanism of a patient in an unstablecondition, for example, under emergency intensive care, and sometimesprovides the opposite effect, or causes body fluids including blood tocoagulate quickly.

The functions of check valves 14 a, 14 b and 14 c will be described.These check valves prevent a sample taken by the body fluid sampler 3 afrom penetrating into unexpected parts due to breakdown, failure,malfunction, and artificial wrong operation of the biologicalcomponent-measuring device. The check valves 14 a, 14 b prevent thesample from flowing back into the calibrating liquid tank 8, even whenthe calibrating liquid channel 11 h is not provided with the first andsecond flow path changeover valves 9 a, 9 b. The check valve 14 b alsokeeps the sample from flowing back into the body fluid-diluting liquidtank 4 a. The check valve 14 c prevents the sample from flowing backinto the flushing liquid tank 13. The advantages of preventing suchbackflows include not only the preclusion of the liquid in each tankfrom contamination but also the prevention of a body fluid fromunnecessarily leaking from a living organism. Especially when the livingorganism is a human, the objective of providing these check valves is toensure the preclusion of a probability that the human's safety may bedamaged. If the channels are wrongly assembled, the flow path changeovervalves are wrongly operated, there is a failure in the channels andequipment, or the human is placed at a higher location than thebiological component-measuring device including the calibrating liquidtank, there is a probability that body fluids, such as blood, may beunexpectedly lost from the human. The check valves are effective inpreventing such accidents. There is also a probability that the firstflow path changeover valve 9 b and the first flow path changeover valve9 a may allow all the relevant channels to communicate, depending on thestructures of the valves, when the valves are switched. The check valves14 a, 14 b, if provided, will be able to prevent backflows also in thesesituations. The channels, through which the sample flows, such as thesample channel 11 a, 11 d, 11 e, 11 o and the waste liquid channel 11 f,may also be provided with check valves, although they are not placed inthis embodiment. These check valves are capable of preventing a bodyfluid from unnecessarily leaking from the living organism as well asprecluding a sample from flowing back into the living organism, thecalibrating liquid tank 8, the body fluid-diluting liquid tank 4 a, theflushing liquid tank 13 or the sensor 5.

An embodiment of the biological component-measuring device according tothe present invention shown in FIG. 3 introduces a diluent into a thirdportion 11 e of the sample channel, which enlarges the measuring rangeof the sensor and improves the stability of the measurement, which, inturn, leads to an improvement in the measuring sensitivity and accuracy.Also, an enlargement of the flow rate can shorten the time necessary forthe sample to reach the sensor, which can reduce the time lag. Thisfeature greatly contributes to the safety of devices, such as artificialendocrine pancreas devices, where a feedback control is carried out, ora liquid medicine in an amount is injected to the patient based on theresults of the measurement, because the feature ensures the stability ofthe control. This embodiment of the body fluid-measuring device furtherincludes a diluent tank 4 b, a first portion 11 i of a first diluentchannel for introducing a diluent from the diluent tank 4 b to a pump 10c, the pump 10 c for drawing the diluent out of the diluent tank 4 b andforcibly sending it to a third portion 11 e of the sample channel, and asecond portion 11 j of the diluent channel through which the diluent issent to the third portion 11 e of the sample channel from the pump 10 c,in addition to the elements of the biological component-measuring deviceshown in FIG. 1. The diluent should preferably introduced into the thirdportion 11 e of the sample channel, located downstream of the pump 10 bfor transferring the sample. A feature of this embodiment is to supply adiluent to the third portion 11 e of the sample channel so that thesample will be in such a desired concentration that the sensitivity andprecision of the sensor are in their best condition. The diluent iscapable of stabilizing the pH of the sample, making the temperature ofthe sample constant, precluding an emission of gas from the sample inthe sensor, and preventing the sample from changing in its properties.The diluent may be anything as long as it does not interfere withmeasurement by the sensor, or change the sample in its properties.Preferable examples may include a physiological saline, a phosphoricacid buffer and the body fluid-diluting liquid as explainedhereinbefore. The phosphoric acid buffer has a function of enhancing theability of transferring electric charges in the diluted sample, andtherefore is an appropriate diluent. The diluent may sometimes include asurfactant. The diluent including a surfactant not only enhances theflow properties of the sample, but also expedites mixing of the samplewith the diluent. The enhancement in the flow properties of the samplereduces the time period from the sampling of a body fluid by the bodyfluid sampler to the measurement of the sampled, or the time constant.

The diluent for, for example, the measurement of a blood sugar level bythe biological component-measuring device according to the presentinvention should preferably be a liquid capable of diluting a sampletransferred through the third portion 11 e of the sample channel, andkeeping the pH value of the sample to be sent to the sensor 5 constant.An example of such a liquid is a phosphoric acid buffer. When a bufferis employed for the diluent, a stable measurement of a blood sugar levelcan by carried out by a highly pH-sensitive sensor because the pH valueof the sample can be kept constant. Also, if a relatively large amountof the diluent whose temperature is kept constant is used, the samplediluted with this diluent can be quickly introduced to the sensor at astable temperature, which improves the accuracy of the measurement.

An embodiment of the biological component-measuring device according tothe present invention shown in FIG. 4 further includes a gas channelthrough which a gas to expedite mixing, such as air, is introduced tothe first diluent channel or the joint of the first diluent channel andthe sample channel, in order to make the mixing of the sample with thediluent complete in the third portion 11 e of the sample channel towhich the diluent has been supplied, in addition to the combination ofthe embodiment of FIG. 2 and the embodiment of FIG. 3. In the mixingpart of the third portion 11 e of the sample channel is placed a mixer15, and at a location downstream of the mixer a gas-liquid separator 16so that the mixture is effectively stirred by the mixer 15 and by theintroduction of air. Gas is separated from the sample that has undergonethe stirring and mixing, by the gas-liquid separator 16, and theseparated gas is removed and discharged through a gas-dischargingchannel 11 p to a waste gas tank 6. Only the sample that has been mixeduniformly is sent to the sensor. If there is an excessive amount of thesample, an unnecessary portion of the sample is also discharged from thegas-liquid separator 16 through the gas-discharging channel 11 p to thewaste gas tank 6. When the sample that has been thoroughly and uniformlymixed with the diluent is sent to the sensor 5, the measuring stabilityof the sensor 5 is enhanced and the measuring sensitivity and themeasuring accuracy are further improved. The sample, after thecompletion of the measurement by the sensor 5, is sucked by a pump 10 fwhose discharge is set to a value less than the total of the dischargeof the pump 10 b and that of the pump 10 c, and discharged to the wasteliquid tank 6. The first diluent channel should preferably be providedwith a check valve 14 d, in the same way as the body fluid-dilutingliquid channel.

FIG. 5 shows an embodiment in which a channel-carrying substrate isdisposed in the embodiment of the biological component-measuring deviceshown in FIG. 4. On the channel-carrying substrate 19 of the embodimentof FIG. 5 are arranged various kinds of channels such as the samplechannel, the body fluid-diluting liquid channel, the first diluentchannel, the second diluent channel, the waste liquid channel, and thegas channel; and a pump tube 10, a channel-joining member 17, the mixer15, and the gas-liquid separator 16 which are placed on the channels. Atleast a part of the sample channel is arranged on the channel-carryingsubstrate 19 of the embodiment according to the present invention. Asexplained hereinbefore, various kinds of channels used in the biologicalcomponent-measuring device, such as the second, third and fourthportions 11 d, 11 e, 11 o of sample channel (see FIG. 4), the firstportion 11 c of the body fluid-diluting liquid channel, the first andsecond portions 11 i, 11 j of the first diluent channel, the seconddiluent channel 11 q, the waste liquid channel 11 f, and the gas channel11 n; and a pump tube 10, the channel-joining member 17, the mixer 15,and the gas-liquid separator 16 which are placed on the channels, shouldbe arranged on the channel-carrying substrate 19. See also FIGS. 4 and 5concerning the reference numerals that denote channels and otherelements.

The embodiment of the biological component-measuring device shown inFIG. 5 will be further described. A body fluid taken through the bodyfluid sampler 3 a is diluted with a body fluid-diluting liquid suppliedfrom the body fluid-diluting liquid tank 4 a. The diluted body fluid isguided to the sensor 5 through the first, second and third portions 11a, 11 d, 11 e of the sample channel. While the diluted body fluid, or asample, is flowing through the sample channel, a diluent and a gas fromthe gas channel are introduced into the third portion 11 e of the samplechannel. The sample and the diluent are mixed thoroughly by the mixer15. The gas and an unnecessary amount of the diluted sample aredischarged from the gas-liquid separator 16, and a proper amount of thediluted sample is guided to the sensor 5. After the completion of themeasurement, the diluted sample is discharged from the sensor 5 throughthe waste liquid channel 11 f to the waste liquid tank 6. When thecalibration is carried out in place of the measurement, the samplechannel and the sensor are flushed out with the flushing liquid in theflushing liquid tank 13 first. Then the first flow path changeover valve9 b and the second flow path changeover valve 9 a are switched so thatthe calibrating liquid is introduced into the device, and the biologicalcomponent-measuring device is calibrated. When a zero point calibrationis carried out, only the diluent is introduced through the seconddiluent channel 11 q to the sensor 5 and the indication of the sensor ischecked. Another way of carrying out the zero point calibration is tosupply the diluent in enough amount to the sensor, prior to the samplingof a body fluid, to fill the channels inside the sensor with thediluent, which provides a zero point calibration. Generally, the zeropoint varies very slightly during a measurement of a biologicalcomponent. Therefore, in many cases, if the zero point calibration isdone once prior to the measurement, it will not be necessary to carryout another zero point calibration until the measurement is completed.When a zero point calibration is not carried out during the measurement,the second diluent channel 11 q and a flow path changeover valve for theswitching to this channel may be omitted. Also, a flushing liquid may beutilized for zero point calibration. The flushing liquid normally doesnot include measured body fluid components. If the flushing pump isactivated and the operation of removing clots in the sample channel iscarried out while the biological component-measuring device is working,the flushing liquid flows into the sensor. If this flushing liquid is aliquid that does not include sugar, such as a physiological saline, orRinger's solution, zero point calibration can be done in a state wherethe body fluid sampler 3 a is connected to a living organism. Forflushing the sensor may be used a calibrating liquid in place of aflushing liquid.

The ends of the channels arranged on the channel-carrying substrate 19are designed so that the ends can be detachably connected to thecorresponding channels, tanks, or equipment such as valves. When thechannel-carrying substrate 19 is attached to the biologicalcomponent-measuring device, these channels are connected with thecorresponding elements. On the other hand, when the channel-carryingsubstrate 19 is detached from the device, the channels are alsodisconnected from the elements. The channel-carrying substrate 19 andthe channels disposed on the substrate 19 can be easily and hygienicallyreplaced with a new one when the examinee 2 is changed or there is aninterval between the preceding measurement and the present measurement.The channel-carrying substrate 19 should be detached from the device inthe following way, so that the leakage of a body fluid during thedetachment will be prevented: The flushing liquid, the bodyfluid-diluting liquid, the calibrating liquid or the diluent isintroduced into the elements on the substrate in which the sampleremains, such as the sample channel, and such elements are washed withone of these liquids prior to the detachment. This channel-carryingsubstrate 19 is generally called “disposable channel-carryingsubstrate”. Materials for the substrate and channels of such adisposable channel-carrying substrate should be inexpensive and easilyavailable, because such disposable channel-carrying substrates usuallyare not used for a long time. Examples of the materials may includerelatively inexpensive resins such as vinyl chloride, polyethylene,polypropylene, polystyrene, polyester, and nylon; and common rubberssuch as natural rubber, butadiene rubber, isoprene rubber, and SBR. Theother elements such as the sensor 5 and the pump 10 d for sending theflushing liquid may be also disposed on the channel-carrying substrate19. However, the fact that the substrate carrying such elements isthrown away raises the cost of a medical examination. An appropriatearrangement of such elements should be selected, with simplicity of theoperation when the channel-carrying substrate is attached to the device,and hygienic care also taken into consideration.

The first portion 11 i of the first diluent channel of the embodimentshown in FIG. 5 is equipped with a heater 15, which is an example ofheating means for heating a diluent. The heater may be anything as longas it is capable of heating a diluent flowing through the first portion11 i of the first diluent channel. This heater 18 serves to control thetemperature of the diluent, which eventually leads to the control of thetemperature of the sample that is introduced into the sensor 5. Thesensor 5 is controlled so as to have the same temperature as the livingorganism under examination, with the safety of the measurementconsidered. When a body fluid is taken from a human examinee, thetemperature is usually set to 36 to 38 degrees Celsius. However, thetemperature of the sample including the body fluid taken from theexaminee often falls, affected by the temperature of the diluent and theatmospheric temperature while it is flowing through the channels. Theeffect of the atmospheric temperature is great, especially when it islow. A low temperature of the sample introduced into the sensor maychange the sensitivity and precision of the sensor. There is also aprobability that air bubbles may be emitted from the sample that sees arapid increase in its temperature in the temperature-controlled sensor,which may disturb the measurement. A method to avoid such a failure isto keep the sample channel warm. However, the body fluid, especiallyblood, is apt to gel or deteriorate when it encounters a highertemperature than the temperature of the interior of the living organism.For example, there is a probability that blood of the human can gel whenit is heated to 40 degrees Celsius or more. For this reason, a stricttemperature control is required so that the temperature of the samplewill not reach 40 degrees Celsius or more, when it is controlled by thewarmed sample channel. On the other hand, the diluent, which does notinclude body fluids, will cause no problems when the temperature thereofis increased to a raised temperature of 50 degrees Celsius. Also, if thediluting ratio of the amount of the diluent to that of the sample is setto a large value, the temperature of the sample at the entrance of thesensor will be easily controlled by the temperature of the diluent. Fromthis viewpoint, this embodiment of the biological component-measuringsensor is provided with the heater 18. Although the heater 18 is placedso that it warms the first portion 11 i of the first diluent channelbetween the diluent tank 4 b and the pump, it may be placed anywhere onthe first diluent channel between the diluent tank 4 b and thechannel-joining member 17, for example a location downstream of thepump. Also, it is a good strategy to additionally warm the samplechannel and the first diluent channel in order to control thetemperature of the sample. However, care should be taken not to heateven apart of the sample excessively when the sample channel is keptwarm.

The method of calibrating the biological component-measuring deviceaccording to the present invention is capable of calibrating not onlythe sensor, but also the entire device, including the channels andpumps, which is different from the conventional calibration of thebiological component-measuring device. The calibration typicallyincludes a zero point calibration carried out with a sample whoseconcentration of sugar, if the component measured is sugar, is zero, anda span calibration carried out for a sample whose concentration ofsugar, if the component measured is sugar, is for example 200 mg/dL. Aworking curve is prepared from the two results and it serves forcorrection of measured values. Generally, variation in the measuredvalue of the concentration used for the span calibration is large, whilevariation in the measured value in the zero point calibration is small.Although the zero point calibration may be omitted, it makes thecalibration more accurate. With FIG. 5 referred to, the device isfurther provided with an additional channel, branched from the seconddiluent channel 11 j, which, in turn, branched from the first portion 11i of the second diluent channel that connected with the second diluenttank 4 b. Through the additional channel, the diluent is directly sentto the sensor 5 from the second diluent channel 11 j. When the zeropoint calibration is carried out, only the diluent is supplied to thesensor 5. The diluent is appropriate to a liquid used for the zero pointcalibration because it does not include affecting components such assugar. In the embodiment shown in FIG. 5, when the process moves on tothe flushing step, which comes just before the calibration step, thezero point calibration of the sensor 5 may be commenced. Before thecommencement, the flow path changeover valve placed just before thesensor 5 is switched to the state that the sensor communicates with thefirst diluent channel, from the state that the sensor communicates withthe sample channel. Then, the diluent is allowed to flow for apredetermined time, for example, about one minute, and thus the zerocalibration is done. If the zero point calibration is commenced at thesame time as the flushing is begun, the time period necessary to carryout the entire step of the calibration can be reduced. If more than twoknown concentrations are used for the calibration, it will provide amore accurate calibration. In this method, span calibrations withseveral concentrations, as well as a zero point calibration, are carriedout, and the working curve is prepared from the results. Naturally, thespan calibrations with several concentrations provide a more preciseworking curve than the former calibration method described above. Forthe latter calibration method may be employed several calibrating liquidtanks 8, in which calibrating liquids in different concentrations arerespectively stored. The calibrating liquids are introduced into thecalibrating liquid channel one by one for the span calibrations.Alternatively, the ratio of the flow rate of the body fluid-dilutingliquid or diluent to that of a single calibrating liquid may be changed,whereby calibrating liquids in different concentrations can be preparedfor the span calibrations. When several calibrating liquid tanks 8 areprepared for the span calibrations, the cross valves for the first andsecond flow path changeover valves 9 a, 9 b may be replaced withfour-way valves or six-way valves to switch the channels respectivelycommunicating with the tanks.

Pumps, tubes for the pumps, and multipumps appropriate for the presentinvention will be explained. The pumps used in the biologicalcomponent-measuring device according to the present invention may bepumps of any type as long as they are capable of transferring therespective liquids each in required amounts at predetermined discharges.Means for sending gas is also called a pump in this specification. Pumpscalled “tube pumps” or “peristaltic pumps”, which are simple in theirstructures and can utilize tubes as the channels as they are, areappropriate for the pumps of the present invention. The pumps will becalled “tube pumps” for convenience's sake. A typical tube pump has, asshown in FIG. 7, rollers 20 a for squeezing elastic and flexible pumptubes 10, which function as the channels, sticks 20 c for supportingthese rollers 20 a, a rotor 20 b for supporting the sticks 20 cconnected thereto and rotating the rollers 20 a, and a holding plate 20d, which tube pump provides the pump tubes with squeezing actions. Therotor 20 b of tube pump rotates around the axis thereof, which, in turn,rotates the rollers 20 a around the rotor 20 b. The rotation of therollers 20 a squeezes the pump tubes 10. The rollers 20 a hold the pumptubes 10 between the rollers and the holding plate 20 d, and squeeze thepump tubes 10, thereby force the liquids in the pump tubes 10 out towardthe downstream side in the tubes as the roller 20 a rotate. The pumptubes 10, which are a part of the channels such as the second portion 11d of the sample channel, double as a part of the pump 10 b. The pumptubes 10, which are a part of the tube pump 20 placed in the channels ofvarious kinds arranged on the channel-carrying substrate 19, are alsodisposed on the same channel-carrying substrate 19. When thechannel-carrying substrate 19 is attached to the biologicalcomponent-measuring device and the device with the substrate is in use,the pump tubes 10, together with the roller 20 a and the holding plate20 d, both of which belong to the biological component-measuring device,and between which the pump tubes 10 are sandwiched, form the tube pump20.

The pump tubes 10 for the channels through which liquids are transferredare arranged parallel with each other on the channel-carrying substrate19, which ensures that all the channels receive the squeezing force andthe liquids in all the channels are forcibly transferred. Each of therollers 20 a of the tube pump 20 is made elongated ones, which arecapable of squeezing all the pump tubes 10 simultaneously by a sameroller 20 a. Then, the flow rates of the respective liquids transferredthrough the channels are decided by the transverse sectional area ofeach pump tube 10 and the rotational speed of the rotor 20 b. When thenumber of the rotor 20 b is one, the flow velocity of the liquid in eachchannel is decided only by the transverse sectional area of the pumptube 10. In other words, the flow rate at which the liquid istransferred by the squeezing of the rollers 20 a can be suitably decidedby an adjustment to the inner diameter of the pump tube 10 in a channel.This type of tube is called “multipump”. Multipumps have a simplestructure and are capable of always keeping constant the ratio of theflow rate of one channel to that of another channel.

Another example of the pump that has the same function as the tube pump20 shown in FIG. 7 is a linear peristaltic pump. Another preferable typeof pump, other than those with the squeezing function, may be a pumpwith a pressing function illustrated in FIG. 8. The pump 21 with apressing function has, as shown in FIG. 8, a lower holding plate 21 dand an upper holding plate 21 e between which pump tubes 10 aresandwiched, a pressing member 21 a capable of projecting from andsinking under the upper face of the lower holding plate 21 d through ahole 21 f pierced in the lower holding plate 21 d, and an eccentricrotating cam 21 b capable of rotating with keeping one end of thepressing member 21 a contacted. When the eccentric rotating cam 21rotates around its rotating shaft 21 c, the pressing member 21 atranslates the rotation into such a vertical movement that the memberprojects from the upper face of the lower holding plate and sinks underit repeatedly through the hole 21 f. On the other hand, the lowerholding plate 21 d may double as the channel-carrying substrate 19. Eachof the fluid channels, such as a sample channel 11 d, is provided with afirst poppet valve 21 g and a second poppet valve 21 h inside the pumptube 10, which also serves as the channel. The upper holding plate 21 eholds the elastic pump tube 10. The compression of the pump tube 10 bythe pressing member 21 a makes smaller the volume of the space insidethe pump tube 10 delimited by the first poppet valve 21 g and the secondpoppet valve 21 h. As a result, the first poppet valve 21 g is closedwhile the second poppet valve 21 h is opened, which makes the fluid inthe pump tube 10 flow out through the second poppet valve 21 h. Thepressing member 21 a starts retracting after the volume of the spaceinside the pump tube 10 reaches the minimum. Then the elasticity of thepump tube 10 returns the volume to its maximum. In this state, the firstpoppet valve 21 g becomes opened while the second poppet valve 21 hbecomes closed, which invites an inflow of the fluid into the delimitedspace of the tube pump 10 through the first poppet valve 21 g. Throughthe repetition of this vertical movement, or the upward-and-downwardmovement of the pressing member 21 a, the inflow of the fluid into thepump tube 10 and the outflow thereof from the tube are repeatedalternately and the fluid is forcibly transferred through the channel.The pump in FIG. 8, in cooperation with the fluid channel that alsoserves as the pump tube 10, makes the fluid flow into and out of thepump tube 10 repeatedly.

The pump for sending a flushing liquid may be a part of the multipumpexplained above. However, one independent pump may be prepared for thepump for sending a flushing liquid, because the discharge of the pump isoften larger than that of the other pumps, for example the pump forsending a sample. Appropriate examples of the pump for sending aflushing liquid may include tube pumps, linear peristaltic pumps, pumpsshown in FIG. 8, diaphragm pumps, and so-called pillow-typereciprocating pumps as shown in FIGS. 11 and 12 which have a swollentube in the pump shown in FIG. 8. These pumps should preferably be thosewith a function of preventing backflow.

There is no special limitation on the material of the channel-carryingsubstrate 19, as long as elements such as those various channels can befixed to the substrate. In this embodiment is employed a hard syntheticresin. Soft and flexible synthetic resins may be used depending on thesituations. Specific examples of the material for the channel-carryingsubstrate 19 are a sheet made of PVC, a hard film of hard PVC or PET,and a soft PVC to which PVC tubes are easily stuck. Although thechannel-carrying substrate 19 may be produced by machining a rawmaterial plate, the production by molding is preferable from theviewpoint of the price of the material, a reduction of waste materialsuch as chips from the machining, and easiness of the mass production.For the molding should be used a method suitable for production in amedium or large quantity, such as compression molding or injectionmolding. The tubes may be fixed to the substrate by sticking them topredetermined locations on the substrate. Another method may be a dieslide injection, often abbreviated to DSI, which is a precision moldingby which the hollow tubes and the substrate are integrally molded. TheDSI method does not require the sticking of the tubes after arrangingthem on the substrate. Still another method that may be utilized isfusible core injection molding in which tubes, each with a core insideit, are molded and the cores are melted away, whereby hollow tubes areprepared. The substrate 3 should preferably be made of an elastic softmaterial so that the substrate will have a certain dimensionaltolerance. The channel-carrying substrate 19 may be attached to themounting face of a biological component-measuring device 1 with pinsand/or hooks. Channel-carrying substrates 19 especially made of suchmaterials as resins with stretching properties can be attached to anddetached from biological component-measuring devices 1 easily, and arepreferably used.

The connection between each channel on the channel-carrying substrate 19as shown in FIG. 5, which is a part of the biologicalcomponent-measuring device, and the corresponding channel outside thesubstrate should preferably be made by a simple removable connector. Forexample, two channels to be connected with each other are formed from asoft material so as to have the shape of a tube, wherein one of thetubes has an inner diameter that is almost the same as the outerdiameter of the other tube. Insertion of the latter tube into the formerone makes the connection. Alternatively, two channels to be connectedwith each other may be formed from a soft material so as to have theshape of a tube, wherein both tubes have the same outer diameter.Another short tube with an inner diameter that is the same as the outerdiameter of the tubes is prepared as a connector, and the respectiveends of the two tubes, which are connected with each other, are insertedinto the connector. A preferable example is a Luer connector often usedto connect tubes made of flexible vinyl chloride. Tubes for the channelsof the present invention are usually manufactured from the economicalviewpoint because the tubes will be exchanged for new ones. Tubes madeof flexible vinyl chloride are suitable for this purpose. Luerconnectors made of flexible vinyl chloride or polycarbonate are easilyconnected with tubes of flexible vinyl chloride, and appropriate for theconnector of the present invention also from the viewpoint of theirproduction cost, a weak probability of leakage of the liquid in thetubes and connector, and a weak probability of slip-off of the tubesfrom the connector. A tube with an end portion, the outer face of whichis in the shape of steps, the shape often called “bamboo sprout”,wherein the outer diameter of the tube decreases stepwise toward itsend, may serve as a simple connector appropriate for the presentinvention. The end of the tube is inserted into the inside of the othertube.

For the mixer 15 various mechanical structures may be employed, as longas they are capable of mixing a sample transferred through the thirdportion 11 e of the sample channel with a diluent, for example a buffer,supplied through the second portion 11 j of the first diluent channel.Even a tube with a certain length may serve as the mixer. Because theforth portion 11 o of the sample channel between the mixer 15 and thesensor 5 is short in the biological component-measuring device,mechanical structures capable of mixing a sample with the diluentsufficiently until the mixture reaches the sensor 5 should preferably beemployed. An example of a preferable mixer 15 may be the one with thestructure whose sectional view is shown in FIG. 9. The mixer 15 has arugged part 15 c comprised of continuous alternate projections anddepressions running in the direction of fluid flow, which rugged part isformed in the inside face of a wall that defines, together with theother walls, an inner fluid flow space 15 b of the mixer proper 15 a inthe shape of a rectangular parallelepiped. The inner fluid flow space 15b communicates with the third portion 11 e of the sample channel, thesecond portion 11 j of the first diluent channel, and the gas channel 11n at a lower part thereof, and with the fourth portion 11 o of thesample channel at an upper part thereof. Another longitudinal sectionalview of the mixer 15 is shown in FIG. 10, which is a view taken alongline A-A in FIG. 9. In FIG. 10, the rugged part 15 c has a centralportion in the form of diamonds. In more detail, the rugged part 15 chas, in the direction of fluid flow, a V-shaped rugged portioncomprising alternate V-shaped projections and V-shaped depressionsfirst. In other words, the first portion of the rugged part has severalV-shaped projections and several V-shaped depressions each betweenadjacent V-shaped projections. Next comes the central portion, which isfollowed by a reverse V-shaped rugged portion comprised of severalprojections in the shaped of a reverse V and several reverse V-shapeddepressions each between adjacent reverse V-shaped projections.

A sample and a diluent introduced into the inside of the mixer proper 15a strike against the first projection of the rugged part 15 c, whichdisturbs the flow of the sample and that of the diluent. The disturbedflows of the sample and the diluent climb over the first projection andfall into the adjacent depression. In the depression the next projectionmakes the flow of the sample and that of the diluent collide, and theflows are disturbed again. Also, the flow of the sample and that of thediluent are divided into a flow component running straight and flowcomponents each running aslant along the walls of the V, since therugged part 15 c has the V-shaped rugged portion and the reverseV-shaped rugged portion. This division of the flows also createsdisturbed flows of the sample and the diluent. The repetition of thedisturbances, caused by crashes of the sample and the diluent againstthe projections and the divisions of the flows into the straightlyrunning components and the aslant running components, mixes the sampleand the diluent.

In the explanation above, only a sample and a diluent are introducedinto the mixer 15. However, the mixer is not limited to this embodiment.For example, a gas inert to samples and diluents, such as air ornitrogen gas, may be introduced into the inner fluid flow space 15 b, tomix a sample and a diluent and to improve the efficiency of the mixing.A schematic block diagram of this embodiment is shown in FIG. 4. Thisembodiment further has a gas channel 11 n, which, as well as the secondportion 11 d of the sample channel, is a flexible tube. The pump tubeportion of the gas channel 11 n is squeezed by the rollers, whereby agas, such as air, in the channel is sent toward the mixer 15. The air ismixed with a diluent in the mixer 15 or upstream of the mixer 15, and asample is further added. In this embodiment, a gas-liquid separator 16is placed downstream of the mixer 15, and the liquid, which is a mixtureof a sample and a diluent, and a gas are separated. The separated gastogether with superfluous liquid is discharged through a gas-dischargingchannel 11 p. Sending air to the mixer 15 in this way improves theefficiency of mixing a sample and a diluent. It also shortens the timeperiod for which a sample is in the mixer 15 and the forth portion 11 oof the sample channel, which makes it possible to measure a sampled bodyfluid quickly.

1. A biological component-measuring device in which a sample including abody fluid taken by a body fluid sampler is transferred to a sensorthrough a sample channel by a pump and a biological component in thesample is measured by the sensor, comprising: a first flow pathchangeover valve placed in the sample channel at a location upstream ofthe pump; and a calibrating liquid channel connected to the first flowpath changeover valve, capable of supplying a calibrating liquid to thesensor through the sample channel by a switching operation of the firstflow path changeover valve.
 2. A biological component-measuring deviceaccording to claim 1, further comprising a body fluid-diluting liquidchannel for supplying a body fluid-diluting liquid to the body fluidsampler.
 3. A biological component-measuring device according to claim1, further comprising: a second flow path changeover valve placed in thebody fluid-diluting liquid channel; and a second body fluid-dilutingliquid channel, connected to the second flow path changeover valve,capable of mixing the body fluid-diluting liquid in the bodyfluid-diluting liquid channel with the calibrating liquid by a switchingoperation of the second flow path changeover valve.
 4. A biologicalcomponent-measuring device according to claim 1, further comprising aflushing liquid channel through which a flushing liquid flows, theflushing liquid channel connected with the sample channel via a thirdflow path changeover valve at a location between the body fluid samplerand the first flow path changeover valve, and/or between the second flowpath changeover valve and the body fluid sampler.
 5. The biologicalcomponent-measuring device according to claim 1, wherein the flushingliquid includes a predetermined concentration of biological components.6. A biological component-measuring device according to claim 1, furthercomprising a first diluent channel through which a diluent for dilutingthe sample in the sample channel flows, the first diluent channelconnected with the sample channel at a location downstream of the firstflow path changeover valve.
 7. A biological component-measuring deviceaccording to claim 6, further comprising a gas channel connected to thefirst diluent channel or a junction of the first diluent channel and thesample channel. 8-15. (canceled)
 16. A method of calibrating thebiological component-measuring device according to claim 1, comprisingtransferring the calibrating liquid from the calibrating liquid channelto the sensor via the sample channel by a switching of the first flowpath changeover valve.
 17. A method of calibrating the biologicalcomponent-measuring device according to claim 6, comprising: a firstoperation of carrying out a zero point calibration of the biologicalcomponent-measuring device by supplying the diluent to the samplechannel from the first diluent channel prior to sampling a biologicalcomponent; a second operation of supplying the flushing liquid to thesample channel while the biological component is being measured; and athird operation of introducing the calibrating liquid in the calibratingliquid channel into the sensor via the sample channel by a switching ofthe first flow path changeover valve, without introducing the flushingliquid into the sensor.
 18. A method of calibrating the biologicalcomponent-measuring device according to claim 4, comprising: a firstoperation of supplying a first portion of the flushing liquid at a firstflow rate that is larger than a flow rate of the sample, to the samplechannel from the flushing liquid channel while a biological component isbeing measured; a second operation of introducing the calibrating liquidinto the sensor by a switching of the first flow path changeover valveplaced in the sample channel, after the first portion of the flushingliquid is introduced into the sample channel and the sensor; and a thirdoperation of introducing a second portion of the flushing liquid at aflow rate smaller than the first flow rate into the sample channel at alocation upstream of the first flow path changeover valve and into thebody fluid sampler during the second operation, to prevent the bodyfluid from flowing into the part filled with the second portion of theflushing liquid.
 19. (canceled)
 20. (canceled)